4-Aminopyrimidines and their use for the antimicrobial treatment of surfaces

ABSTRACT

Use of 4-aminopyrimidines of formula (1), wherein R 1 , R 2 , R 3 , R 4  and R 5  are as described in the description in the antimicrobial treatment of surfaces.

The present invention relates to substituted 4-aminopyrimidines, to thepreparation of such compounds, and to the use of such compounds in theantimicrobial treatment of surfaces, as antimicrobial active substancesagainst gram-positive and gram-negative bacteria, yeasts and fungi andalso in the preservation of cosmetics, household products, textiles andplastics and for use in disinfectants.

The present invention relates to the use of 4-aminopyrimidines offormula

-   -   R₁ and R₂ are each independently of the other hydrogen;        C₁-C₅alkyl which is unsubstituted or substituted by one or more        halogen atoms; biphenyl or C₆-C₁₀aryl which is unsubstituted or        substituted by halogen, C₁-C₅alkyl, C₁-C₅alkoxy or by amino; a        5- to 7-membered heteroaryl radical; or cyclo-C₃-C₇alkyl;    -   R₃ is hydrogen; phenyl or C₁-C₅alkyl which is unsubstituted or        substituted by one or more halogen atoms;    -   R₄ is hydrogen; C₁-C₁₀alkyl; phenyl; or a 5- to 7-membered        heteroaryl radical;    -   R₅ is C₁-C₂₀alkyl which is unsubstituted or substituted by one        or more halogen atoms or by a heterocyclic radical or        interrupted by one or more —O— or    -    groups or by a bivalent heterocyclic radical; NR″R′″-C₁-C₁₀        alkyl which is unsubstituted or substituted by a heterocyclic        radical or interrupted by one or more —O— or    -    groups or by a bivalent heterocyclic radical; cyclo-C₅-C₈alkyl;        hydroxy-C₁-C₂₀alkyl; phenyl-C₁-C₃alkyl; a heterocyclic radical;        or    -   R₄ and R₅, together with the nitrogen atom linking them, form a        radical of    -   R′ is hydrogen; or C₁-C₃alkyl;    -   R″ and R′″ are each independently of the other hydrogen;        C₁-C₅alkyl; or hydroxy-C₁-C₅alkyl;    -   X is    -   R″″ is hydrogen; C₁-C₄alkyl; or heteroaryl-C₁-C₄alkyl; and    -   n₁ and n₂ are each independently of the other from 1 to 8;        in the antimicrobial treatment of surfaces.

C₁-C₂₀Alkyl radicals are straight-chain or branched alkyl radicals, forexample methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, amyl, isoamyl or tert-amyl, heptyl, octyl, isooctyl, nonyl,decyl, undecyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,octadecyl or eicosyl.

C₃-C₁₀Cycloalkyl denotes, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl orcyclodecyl. Those radicals may be substituted, for example by one ormore identical or different C₁-C₄alkyl radicals, especially by methyl,and/or by hydroxy. When cycloalkyl radicals are substituted by one ormore substituents, they are substituted preferably by one, two or four,especially by one or two, identical or different substituents.

C₁-C₅Alkoxy radicals are straight-chain or branched radicals such as,for example, methoxy, ethoxy, propoxy, butoxy or pentyloxy.

C₆-C₁₀Aryl and heteroaryl radicals may be unsubstituted or may carry oneor more, for example one, two, three or four, identical or differentsubstituents, which may be located in any positions. Examples of suchsubstituents are, for example, C₁-C₄alkyl, halogen, hydroxy,C₁-C₄alkoxy, trifluoromethyl, cyano, hydroxycarbonyl,C₁-C₄alkoxycarbonyl, aminocarbonyl, amino, C₁-C₄allylamino,di-C₁-C₄alkylamino and C₁-C₄alkylcarbonylamino.

Heteroaryl radicals are derived from heterocycles containing one, two,three or four identical or different ring hetero atoms, especially fromheterocycles containing one, two or three, more especially one or two,identical or different hetero atoms. The heterocycles may be mono- orpoly-cyclic, for example mono-, bi- or tri-cyclic. They are preferablymono- or bi-cyclic, especially monocyclic. The rings preferably contain5, 6 or 7 ring members. Examples of monocyclic and bicyclic heterocyclicsystems from which radicals occurring in the compounds of formula (1)can be derived are, for example, pyrrole, furan, thiophene, imidazole,pyrazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine,pyrimidine, pyrazine, pyran, thiopyran, 1,4-dioxane, 1,2-oxazine,1,3-oxazine, 1,4-oxazine, indole, benzothiophene, benzofuran,pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.

Unsaturated heterocycles may contain, for example, one, two or threeunsaturated double bonds in the ring system. 5-membered rings and6-membered rings in monocyclic and polycyclic heterocycles may also be,especially, aromatic.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine orchlorine.

In accordance with the invention, preference is given to the use ofcompounds of formula (1) wherein

-   -   R₅ is R″R′″N-C₁-C₂₀alkyl which is uninterrupted or interrupted        by one or more —O— or    -    groups or by a bivalent heteroyclic radical;    -   R′ is hydrogen; or C₁-C₅alkyl;    -   R″ and R′″ are each independently of the other hydrogen; or        methyl; and    -   R₁, R₂, R₃and R₄ are as defined for formula (1).

Very special preference is given to the use of compounds of formula (1)wherein R₅ is R″R′″N-C₁-C₂₀alkyl which is uninterrupted or interruptedby

In accordance with the invention, there are furthermore used compoundsof formula (1) wherein

-   -   R₅ is R″R′″N-C₅-C₂₀alkyl which is uninterrupted or interrupted        by one or more —O— or    -    groups;    -   R′ is hydrogen; or C₁-C₅alkyl; and    -   R″ and R′″ are each independently of the other hydrogen; or        methyl.

Among those compounds, preference is given to those wherein

-   -   R₅ is R″R′″N-C₁-C₅alkyl; and    -   R″ and R′″ are each independently of the other hydrogen; or        methyl.

Very special preference is also given to the use of compounds of formula(1) wherein

-   -   R₄ is hydrogen; or C₁-C₅alkyl;    -   R₅ is C₅-C₂₀alkyl which is unsubstituted or interrupted by —NH—;        and    -   R₁, R₂ and R₃ are as defined for formula (1);    -   especially compounds of formula (1) wherein    -   R₁ is hydrogen; C₁-C₅alkyl; unsubstituted or        C₁-C₄alkyl-substituted phenyl or phenyl-C₁-C₄alkyl; or pyridino;    -   R₂ is hydrogen; or C₁-C₅alkyl; especially methyl;    -   R₃ is hydrogen; or C₁-C₅alkyl;    -   R₄ is hydrogen; or C₁-C₅alkyl; and    -   R₅ is C₅-C₂₀alkyl;    -   and very especially compounds of formula (1) wherein    -   R₁ is hydrogen; C₁-C₅alkyl, especially isopropyl or methyl;        unsubstituted or C₁-C₄alkyl-substituted phenyl; or pyridino;    -   R₂ is methyl;    -   R₃ and R₄ are hydrogen; and    -   R₅ is C₈-C₁₈alkyl.

Among the last-mentioned compounds very special preference is given tothe use of those wherein

-   -   R₅ is linear C₈-C₁₈alkyl.

Also preferably used are compounds of formula (1) wherein, in formula(1a),

-   -   R″″ is hydrogen; or pyridyl-C₁-C₃alkyl; and    -   n₁ and n₂ are each 2.

Preference is also given to the use of compounds of formula (1) wherein

-   -   R₁ and R₂ are each independently of the other hydrogen;        C₁-C₅alkyl; phenyl which is unsubstituted or substituted by        halogen, C₁-C₅alkyl, C₁-C₅alkoxy or by amino; biphenyl;        cyclo-C₃-C₇alkyl; 3-pyridyl; 4-pyridyl; 2-thiophenyl;        3-thiophenyl; or thiazolyl;    -   or compounds of formula (1) wherein    -   R₃ is hydrogen; or phenyl;    -   or compounds of formula (1) wherein    -   R₄ is hydrogen.

Special preference is given to the use of compounds of formula

wherein

-   -   X is —O—; or    -   R′ is hydrogen; or C₁-C₃alkyl;    -   n is 1-3; and    -   m is 1-3;        and    -   R₁, R₂ and R₃ are as defined for formula 1.

The Table that follows lists, by way of example, further4-aminopyrimidines according to the invention: Comp. of Purity [%]Purity [%] formula Structural formula 254 nm 280 nm 3

64 72 4

37 96 5

83 97 6

92 97 7

43 48 8

82 93 9

94 98 10

49 59 11

75 89 12

95 97 13

94 99 14

91 97 15

91 98 16

42 44 17

39 43 18

42 51 19

64 70 20

63 77 21

70 82 22

51 65 23

67 82 24

95 97 25

88 96 26

81 90 27

88 93 28

86 93 29

61 62 30

85 72 31

45 42 32

69 64 33

94 93 34

89 89 35

92 88 36

82 73 37

82 66 38

56 34 39

67 46 40

43 44 41

81 77 42

91 92 43

72 68 44

88 84 45

82 83 46

88 88 47

72 67 48

81 85 49

92 84 50

84 86 51

77 73 52

88 91 53

87 89 54

90 91 55

85 87 56

87 84 57

99 99 58

58 78 59

34 64 60

46 32 61

90 87 62

66 61 63

99 95 64

80 80 65

96 92 66

90 95 67

48 44 68

37 38 69

64 79 70

71 82 71

88 88 72

79 52 73

90 96 74

79 39 75

92 89 76

97 95 77

86 90 78

90 94 79

92 95 80

54 50 81

40 42 82

67 84 83

77 72 84

93 91 85

83 80 86

92 92 87

95 94 88

94 95 89

92 90 90

54 33 91

89 95 92

52 48 93

40 39 94

65 80 95

82 83 96

78 85 97

31 26 98

79 60 99

93 90 100

71 59 101

87 78 102

49 25 103

89 89 104

54 41 105

33 38 106

65 75 107

80 82 108

87 96 109

87 87 110

90 94 111

94 92 112

87 90 113

92 85 114

41 28 115

93 96 116

58 46 117

39 40 118

54 70 119

82 87 120

42 35 121

87 90 122

78 87 123

68 73 124

93 96 125

93 93 126

87 86 127

65 69 128

46 52 129

58 69 130

82 83 131

73 74 132

88 90 133

94 93 134

100 89 135

92 91 136

92 92 137

49 44 138

41 41 139

50 66 140

100 80 141

74 71 142

100 83 143

84 79 144

62 54 145

43 39 146

34 35 147

61 73 148

72 70 149

91 89 150

87 88 151

88 86 152

91 83 153

89 85 154

94 85 155

85 81 156

86 82 157

62 63 158

86 92 159

89 91 160

88 92 161

87 92 162

67 88 163

67 66 164

85 92 165

81 92 166

68 75 167

92 89 168

72 73 169

87 83 170

77 85 171

86 81 172

87 72 173

69 67 174

66 87 175

69 64 176

82 57 177

87 92 178

77 69 179

77 85

The 4-aminopyrimidines used in accordance with the invention areprepared by methods known per se (J. Org. Chem.; 1967, 32, 1591). Forthat purpose, a cyano compound (R₁—C≡N) is reacted, in a suitablesolvent such as, for example, methanol, ethanol, isopropanol, DMF,tetrahydrofuran etc., with ammonium acetate or ammonium chloride at atemperature of from −10° C. to 100° C. over a period of from 1 hour to24 hours to form the corresponding amidine compound

The amidine compound is then condensed with ari appropriate β-keto ester

using an auxiliary base such as, for example, sodium carbonate,potassium hydroxide, sodium ethanolate, sodium methanolate, potassiumtert-butanolate etc., in a suitable solvent such as, for example,methanol, ethanol, butanol, tert-butanol, THF, DMF, acetonitrile,toluene, xylene etc., over a period of from 1 to 24 hours at atemperature of from 40 to 120° C.

The 4-hydroxy-2-pyrimidine compound

thereby obtained is then converted into the corresponding4-chloro-2-pyrimidine compound

by conventional methods using phosphorus oxychloride.

The substituted 4-aminopyrimidines

are obtained by reacting the 4-chloro-2-pyrimidine compound with aprimary or secondary amine (R₄R₅NH) in a suitable solvent such as, forexample, DMF, dioxane, toluene, xylene, ethanol, butanol, and anauxiliary base such as, for example, triethylamine, DIEA, sodiumcarbonate, potassium hydroxide etc., or using an excess of amine at from40 to 130° C. over a period of from 1 to 24 hours.

The entire reaction proceeds according to the following scheme:

R₁, R₂, R₃, R₄ and R₅ being as defined for formula (1).

Preparation of the compounds of formula (2) is carried out by reactingan excess of from 2 to 10 equivalents of the diamine compoundH₂N(CH₂)_(n)X(CH₂)_(m)NH₂ in, for example, DMF, dichloromethane, THF ordioxane with trityl chloride polystyrene resin at a temperature of from10 to 50° C. over a period of from 0.5 to 24 hours. From 2 to 10equivalents of the appropriately substituted 4,6-dichloropyrimidines

are then reacted, in a suitable solvent such as, for example,dichloromethane, DMF, THF or toluene, with the polymer-bound diamines atfrom 10 to 120° C. over a period of from 2 to 48 hours. The4-chloropyrimidines are reacted with from 2 to 10 equivalents of variousboronic acids, from 1 to 10% of palladium catalyst and from 2 to 10equivalents of auxiliary base such as, for example, CaCO₃ and NaCO₃, in,for example, THF, DMF or dioxane. After washing the resin to remove theexcess, the target compounds are split off using from 1 to 30%trifluoroacetic acid (TFA) In dichloromethane (DCM) at 25° C. over aperiod of from 1 to 5 hours. For the purpose of further purification,the substances are freeze-dried from tBuOH/water 4:1 with from 1 to 10%HOAc and once from tBuOH/water 4:1.

The entire reaction proceeds according to the following scheme:

R₁, R₂, R₃, X, m and n being as defined for formula (2).

Some of the 4-aminopyrimidines used in accordance with the invention areknown from the literature and some are novel compounds. The inventionrelates also to those novel compounds.

The novel compounds correspond to formula

-   -   R₁ and R₂ are each independently of the other hydrogen;        C₁-C₅alkyl which is unsubstituted or substituted by one or more        halogen atoms; biphenyl or C₆-C₁₀aryl which is unsubstituted or        substituted by halogen, C₁-C₅alkyl, C₁-C₅alkoxy or by amino; a        5- to 7-membered heteroaryl radical; or cyclo-C₃-C₇alkyl;    -   R₃ is hydrogen; phenyl or C₁-C₅alkyl which is unsubstituted or        substituted by one or more halogen atoms;    -   R₄ is hydrogen; C₁-C₁₀alkyl; phenyl; or a 5- to 7-membered        heteroaryl radical;    -   R₅ is C₁-C₂₀alkyl which is unsubstituted or substituted by one        or more halogen atoms or by a heterocyclic radical or        interrupted by one or more —O— or    -    groups or by a bivalent heterocyclic radical;        NR″R′″-C₁-C₂₀alkyl which is unsubstituted or substituted by a        heterocyclic radical or interrupted by one or more —O— or    -    groups or by a bivalent heterocyclic radical; cyclo-C₅-C₈alkyl;        hydroxy-C₁-C₂₀alkyl; phenyl-C₁-C₃alkyl; a heterocyclic radical;        or    -   R₄ and R₅, together with the nitrogen atom linking them, form a        radical of    -   R′ is hydrogen; or C₁-C₃alkyl;    -   R″ and R′″are each independently of the other hydrogen;        C₁-C₅alkyl; or hydroxy-C₁-C₅alkyl;    -   X is    -   R″″ is hydrogen; C₁-C₄alkyl; or heteroaryl-C₁-C₄alkyl; and    -   n₁ and n₂ are each independently of the other from 1 to 8;    -   not including compounds of formula (1′) wherein simultaneously    -   R₁ is C₆-C₁₀aryl; or C₁-C₄alkyl; and    -   R₅ is C₁-C₇alkyl.

The 4-aminopyrimidines used in accordance with the invention exhibitpronounced antimicrobial action, especially against pathogenicgram-positive and gram-negative bacteria and against bacteria of theskin flora, and also against yeasts and moulds. They are accordinglysuitable especially for disinfection, deodorisation, and for general andantimicrobial treatment of the skin and mucosa and of integumentaryappendages (hair), more especially for the disinfection of hands andwounds.

They are accordingly suitable as antimicrobial active substances andpreservatives in personal care preparations such as, for example,shampoos, bath additives, haircare preparations, liquid and solid soaps(based on synthetic surfactants and salts of saturated and/orunsaturated fatty acids), lotions and creams, deodorants, other aqueousor alcoholic solutions, e.g. cleansing solutions for the skin, moistcleaning cloths, oils or powders.

The invention accordingly relates also to a personal care preparationcomprising at least one compound of formula (1) and cosmeticallytolerable carriers or adjuvants.

The personal care preparation according to the invention contains from0.01 to 15% by weight, preferably from 0.1 to 10% by weight, based onthe total weight of the composition, of a compound of formula (1), andcosmetically tolerable adjuvants.

Depending upon the form of the personal care preparation, it comprises,in addition to the 4-aminopyrimidine of formula (1), furtherconstituents such as, for example, sequestering agents, colorants,perfume oils, thickeners or solidifiers (consistency regulators),emollients, UV-absorbers, skin protective agents, antioxidants,additives that improve the mechanical properties, such as dicarboxylicacids and/or aluminium, zinc, calcium or magnesium salts of C₁₄-C₂₂fattyacids, and, optionally, preservatives.

The personal care preparation according to the invention may be in theform of a water-in-oil or oil-in-water emulsion, an alcoholic oralcohol-containing formulation, a vesicular dispersion of an ionic ornon-ionic amphiphilic lipid, a gel, a solid stick or an aerosolformulation.

As a water-in-oil or oil-in-water emulsion, the cosmetically tolerableadjuvant contains preferably from 5 to 50% of an oil phase, from 5 to20% of an emulsifier and from 30 to 90% water. The oil phase maycomprise any oil suitable for cosmetic formulations such as, forexample, one or more hydrocarbon oils, a wax, a natural oil, a siliconeoil, a fatty acid ester or a fatty alcohol. Preferred mono- or poly-olsare ethanol, isopropanol, propylene glycol, hexylene glycol, glyceroland sorbitol.

Cosmetic formulations according to the invention are used in variousfields. There come into consideration, for example, especially thefollowing preparations:

-   -   skin-care preparations, e.g. skin-washing and cleansing        preparations in the form of tablet-form or liquid soaps,        synthetic detergents or washing pastes,    -   bath preparations, e.g. liquid (foam baths, milks, shower        preparations) or solid bath preparations, e.g. bath cubes and        bath salts;    -   skin-care preparations, e.g. skin emulsions, multi-emulsions or        skin oils;    -   cosmetic personal care preparations, e.g. facial make-up in the        form of day creams or powder creams, face powder (loose or        pressed), rouge or cream make-up, eye-care preparations, e.g.        eyeshadow preparations, mascaras, eyeliners, eye creams or        eye-fix creams; lip-care preparations, e.g. lipsticks, lip        gloss, lip contour pencils, nail-care preparations, such as nail        varnish, nail varnish removers, nail hardeners or cuticle        removers;    -   intimate hygiene preparations, e.g. intimate washing lotions or        intimate sprays;    -   foot-care preparations, e.g. foot baths, foot powders, foot        creams or foot balsams, special deodorants and antiperspirants        or callus-removing preparations;    -   light-protective preparations, such as sun milks, lotions,        creams or oils, sun-blocks or tropicals, pre-tanning        preparations or after-sun preparations;    -   skin-tanning preparations, e.g. self-tanning creams;    -   depigmenting preparations, e.g. preparations for bleaching the        skin or skin-lightening preparations;    -   insect-repellents, e.g. insect-repellent oils, lotions, sprays        or sticks; deodorants, such as deodorant sprays, pump-action        sprays, deodorant gels, sticks or roll-ons;    -   antiperspirants, e.g. antiperspirant sticks, creams or roll-ons;    -   preparations for cleansing and caring for blemished skin, e.g.        synthetic detergents (solid or liquid), peeling or scrub        preparations or peeling masks;    -   hair-removal preparations in chemical form (depilation), e.g.        hair-removing powders, liquid hair-removing preparations, cream-        or paste-form hair-removing preparations, hair-removing        preparations in gel form or aerosol foams;    -   shaving preparations, e.g. shaving soap, foaming shaving creams,        non-foaming shaving creams, foams and gels, preshave        preparations for dry shaving, aftershaves or aftershave lotions;    -   fragrance preparations, e.g. fragrances (eau de Cologne, eau de        toilette, eau de parfum, parfum de toilette, perfume), perfume        oils or perfume creams;    -   dental care, denture-care and mouth-care preparations, e.g.        toothpastes, gel toothpastes, tooth powders, mouthwash        concentrates, anti-plaque mouthwashes, denture cleaners or        denture fixatives;    -   cosmetic hair-treatment preparations, e.g. hair-washing        preparations in the form of shampoos and conditioners, hair-care        preparations, e.g. pretreatment preparations, hair tonics,        styling creams, styling gels, pomades, hair rinses, treatment        packs, intensive hair treatments, hair-structuring preparations,        e.g. hair-waving preparations for permanent waves (hot wave,        mild wave, cold wave), hair-straightening preparations, liquid        hair-setting preparations, hair foams, hairsprays, bleaching        preparations, e.g. hydrogen peroxide solutions, lightening        shampoos, bleaching creams, bleaching powders, bleaching pastes        or oils, temporary, semi-permanent or permanent hair colorants,        preparations containing self-oxidising dyes, or natural hair        colorants, such as henna or camomile.

An antimicrobial soap has, for example, the following composition:

-   -   0.01 to 5% by weight of a compound of formula (1)    -   0.3 to 1% by weight titanium dioxide,    -   1 to 10% by weight stearic acid,    -   soap base ad 100%, e.g. a sodium salt of tallow fatty acid or        coconut fatty acid, or glycerol.

A shampoo has, for example, the following composition:

-   -   0.01 to 5% by weight of a compound of formula (1),    -   12.0% by weight sodium laureth-2-sulfate,    -   4.0% by weight cocamidopropyl betaine,    -   3.0% by weight NaCl and    -   water ad 100%.

A deodorant has, for example, the following composition:

-   -   0.01 to 5% by weight of a compound of formula (1),    -   60% by weight ethanol,    -   0.3% by weight perfume oil, and    -   water ad 100%.

The invention relates also to an oral composition containing from 0.01to 15% by weight, based on the total weight of the composition, of acompound of formula (1), and orally tolerable adjuvants.

Example of an oral composition:

-   -   10% by weight sorbitol,    -   10% by weight glycerol,    -   15% by weight ethanol,    -   15% by weight propylene glycol,    -   0.5% by weight sodium lauryl sulfate,    -   0.25% by weight sodium methylcocyl taurate,    -   0.25% by weight polyoxypropylene/polyoxyethylene block        copolymer,    -   0.10% by weight peppermint flavouring,    -   0.1 to 0.5% by weight of a compound of formula (1), and    -   48.6% by weight water.

The oral composition according to the invention may be, for example, inthe form of a gel, a paste, a cream or an aqueous preparation(mouthwash).

The oral composition according to the invention may also comprisecompounds that release fluoride ions which are effective against theformation of caries, for example inorganic fluoride salts, e.g. sodium,potassium, ammonium or calcium fluoride, or organic fluoride salts, e.g.amine fluorides, which are known under the trade name Olafluor.

The 4-aminopyrimidines of formula (1) used in accordance with theinvention are also suitable for treating, especially preserving, textilefibre materials. Such materials are undyed and dyed or printed fibrematerials, for example of silk, wool, polyamide or polyurethanes, andespecially cellulosic fibre materials of all kinds. Such fibre materialsare, for example, natural cellulose fibres, such as cotton, linen, juteand hemp, as well as cellulose and regenerated cellulose. Preferredsuitable textile fibre materials are made of cotton.

The 4-aminopyrimidines according to the invention are suitable also fortreating, especially imparting antimicrobial properties to orpreserving, plastics such as, for example, polyethylene, polypropylene,polyurethane, polyester, polyamide, polycarbonate, latex etc. Fields ofuse therefor are, for example, floor coverings, plastics coatings,plastics containers and packaging materials; kitchen and bathroomutensils (e.g. brushes, shower curtains, sponges, bathmats), latex,filter materials (air and water filters), plastics articles used in thefield of medicine such as, for example, dressing materials, syringes,catheters etc., so-called “medical devices”, gloves and mattresses.

Paper, for example papers used for hygiene purposes, may also beprovided with antimicrobial properties using the 4-aminopyrimidinesaccording to the invention.

It is also possible for nonwovens such as, for example, nappies/diapers,sanitary towels, panty liners, and cloths for hygiene and householduses, to be provided with antimicrobial properties in accordance withthe invention.

The 4-aminopyrimidines of formula (1) are also used in washing andcleaning formulations such as, for example, liquid or powder washingagents or softeners.

The 4-aminopyrimidines of formula (1) can also be used especially inhousehold and general-purpose cleaners for cleaning and disinfectinghard surfaces.

A cleaning preparation has, for example, the following composition:

-   -   0.01 to 5% of a compound of formula (1)    -   3.0% octyl alcohol 4EO    -   1.3% fatty alcohol C₈-C₁₀polyglucoside    -   3.0% isopropanol    -   water ad 100%.

In addition to preserving cosmetic and household products, thepreservation of technical products, the provision of technical productswith antimicrobial properties and use as a biocide in technicalprocesses are also possible, for example in paper treatment, especiallyin paper treatment liquors, printing thickeners of starch or cellulosederivatives, surface-coatings and paints.

The 4-aminopyrimidines of formula (1) are also suitable for theantimicrobial treatment of wood and for the antimicrobial treatment ofleather, the preserving of leather and the provision of leather withantimicrobial properties.

The compounds according to the invention are also suitable for theprotection of cosmetic products and household products from microbialdamage.

The following Examples illustrate, but do not limit, the presentinvention.

IMPLEMENTATION EXAMPLES

General Work Procedure for Parallel Synthesis of 4-Aminopyrimidines:

Example 1

Preparation of 4-chloro-6-methyl-2-phenylpyrimidine

2.2 g of benzamidine hydrochloride (14.05 mmol) are reacted, in 10 ml ofabsolute EtOH, with 5.43 ml (14.05 mmol) of 20% sodium ethanolatesolution and then condensed with 1.66 g of methyl acetoacetate (14.29mmol) for 4 hours at 90° C. The crude product is concentrated byevaporation and taken up in 30 ml of toluene. 4.31 g of phosphorusoxychloride (28.1 mmol) are added and the reaction mixture is heated at120° C. for 3 hours. After cooling to 20° C., the excess is neutralisedwith sodium hydroxide solution, and the mixture is diluted with ethylacetate and then washed with water and saturated sodium chloridesolution.

The product solution is dried over sodium sulfate and concentrated byevaporation. 2.2 g of 4-chloro-6-methyl-2-phenylpyrimidine (77.7% oftheory) are obtained.

Example 2 Reaction of 4-chloro-6-methyl-2-phenylpyrimidine withmonoamines

20.5 mg of 4-chloro-6-methyl-2-phenylpyrimidine (0.1 mmol) are heatedwith 3 equivalents of monoamines (0.3 mmol) in 0.5 ml of absolutedioxane at 100° C. for 20 hours. After cooling, the products areconcentrated in vacuo, taken up in t-BuOH/water 4/1 and freeze-dried.The end products are analysed by LC-MS.

Example 3 Loading of trityl chloride polystyrene resin withN,N-bis(3-aminopropyl)methylamines and reaction with4,6-dichloro-2,5-diphenylpyrimidine

In each case, 50 mg of resin (1.29 mmol/g) are shaken in 1 ml of DMFwith 94 mg of N,N-bis(3-aminopropyl)methylamine (0.645 mmol) at 25° C.for 3 hours. The resin is filtered off and washed with DCM, MeOH, THF,MeOH and DCM and dried in vacuo.

The resin is shaken in 1 ml of DMF with 0.194 g of4,6-dichloro-2,5-diphenylpyrimidine (0.645 mmol) and 90 μl oftriethylamine (0.645 mmol) at 25° C. for 3 hours.

The resin is filtered off and washed with DCM, MeOH, THF, MeOH, DCM andMeOH and dried in vacuo.

Example 4 Parallel reaction of4-amino-6-chloro-1,5-diphenylpyrimidine-TCP resins with various boronicacids and splitting off

The resin is heated with 126.1 g of caesium carbonate (6 eq., 0.387mmol) and 300 μL of a toluene solution of 0.1 eq. of a palladiumcatalyst (WO 01/16057) at 95° C. for 15 minutes. After adding 3 eq. of aboronic acid, dissolved in 700 μl of toluene solution, the mixture isheated at 90° C. for 1 hour.

After cooling, the resin is filtered off and washed with DMF, MeOH, THF,MeOH and DCM and dried in vacuo.

The products are split off using 1.5 ml of a 5% TFA/DCM solution at roomtemperature for 3 hours. The resin is then washed with 1 ml of DCM and 1ml of MeOH, and the combined solutions are concentrated to dryness byevaporation. The end products are analysed by LC-MS.

Example 5 Preparation of 4-chloro-6-methyl-2-tolylpyrimidine

2.5 g of 4-methyl-benzamidine hydrochloride (14.65 mmol) are reacted in10 ml of absolute EtOH with 5.66 ml of a 20% solution of sodiumethanolate (14.65 mmol) and then condensed with 1.73 g of methylacetoacetate (14.88 mmol) at 90° C. for 4 hours. The crude product isconcentrated by evaporation and taken up in 30 ml of toluene. 6.74 g ofphosphorus oxychloride (44.0 mmol) are added and the reaction mixture isheated at 120° C. for 3 hours. After cooling to 20° C., the excess isneutralised with sodium hydroxide solution, and the mixture is dilutedwith ethyl acetate, washed with saturated sodium hydrogen carbonatesolution and then with water. The product solution is concentrated byevaporation and separated by column chromatography (hexane/EE: 5/1). 2.1g of 4-chloro-6-methyl-2-tolylpyrimidine (66.5% of theory) are obtained.

NMR: 1H (ppm in DMSO): 2.4, s, 3H; 2.55, s, 3H; 7.3, d, 2H; 7.5, s, 1H;8.25, d, 2H

Example 6 Reaction of 4-chloro-6-methyl-2-(4-methyl)-phenylpyrimidinewith monoamines

21.9 mg of 4-chloro-6-methyl-2-(4-methyl)-phenylpyrimidine (0.1 mmol)are heated with 3 eq. of monoamines (0.3 mmol) in 0.5 ml of absolutedioxane at 100° C. for 20 hours. After cooling, the products areconcentrated in vacuo, taken up in t-BuOH/water 4/1 and freeze-dried.The end products are analysed by LC-MS.

Example 7 Reaction of 4-chloro-6-methyl-2-(4-methyl)-phenylpyrimidinewith octylamine

1.36 g of 4-chloro-6-methyl-2-(4-methyl)-phenylpyrimidine (6.23 mmol)are heated with 886 mg of octylamine (6.85 mmol) and 2.58 g of potassiumcarbonate (18.68 mmol) in 10 g of dioxane at 100° C. for 48 hours. Aftercooling, the product is taken up in 100 ml of ethyl acetate and washedwith sodium hydroxide solution 0.5 mol/l, saturated sodium hydrogencarbonate solution and water. The product is concentrated in vacuo,taken up in t-BuOH/water 4/1 and freeze-dried.

1.92 g of 4-chloro-6-methyl-2-(4-methyl)-phenylpyrimidine (6.15 mmol,98.7% of theory) are obtained.

The end product is analysed by NMR, GC-MS and GC.

NMR 1H (ppm in DMSO): 0.9, t, 3H; 1.25, m, 12H; 1.55, m, 2H; 2.25, s,3H; 2.3, s, 3H; 6.4, s, 1H; 7.1, m, 1H; 7.2, d, 2H; 8.2, d, 2H;(m/z=311);

GC: 95% purity

Example 8 Preparation of 4-chloro-2-isopropyl-6-methylpyrimidine

76.1 g of 2-isopropyl-6-methyl-4-pyrimidinol [2814-20-2] (500 mmol) aredissolved in 300 ml of toluene at 90° C. 80.5 g of phosphorusoxychloride (525 mmol) are added dropwise thereto at from 90 to 103° C.,and the reaction mixture is heated at 110° C. for 2 hours. After coolingto 20° C., the reaction mixture is adjusted to pH 8 using 4M sodiumhydroxide solution, with cooling. The aqueous phase is separated off andextracted with 100 ml of toluene. The combined organic phases are washedthree times with 100 ml of water each time and dried at RT under 2 mbar.89.7 g (105%; contains toluene) are obtained.

Example 9 Preparation of 4-dodecylamino-2-isopropyl-6-methylpyrimidine(compound of formula (93)

79.2 g of 4-chloro-2-isopropyl-6-methylpyrimidine (464.1 mmol) areheated in 100 ml of dioxane at 100° C. A heated solution of 189.3 g ofdodecylamine (1021 mmol, 2.2 eq) in 30 ml of dioxane is added dropwisethereto over the course of 2 hours, and the reaction mixture is furtherheated for 2 hours at 100° C. and for 9 hours at 109° C. After cooling,400 ml of ethyl acetate and 150 ml of 4M sodium hydroxide solution (600mmol) are added thereto and the mixture is stirred at 50° C. for 10minutes. The lower, aqueous phase is discarded, the organic phase iswashed with 300 ml of water, and 10 ml of saturated NaCl solution areadded thereto. The organic phase is separated off and concentrated, andthe excess dodecylamine is distilled in vacuo up to a bath temperatureof 160° C. 136.1 g (91.8%); GC purity: 98%

NMR 1H (ppm in CDCl₃): 0.7, t, 3H; 1.1, m, 24H; 1.4, m, 2H; 2.15, s, 3H;2.75,Q, 1 H; 3.05, m, 2H; 4.9, s, 1 H; 5.8, s, 1H

Example 10 Determination of the Minimum Inhibitory Concentration (MICValue) in Microtitre Plates

Nutrient Medium:

Casein/soymeal peptone broth for preparation of pre-cultures of testbacteria and yeast

Examples of Test Organisms:

-   -   Bacteria: Pseudomonas aeruginosa CIP A-22 (=PA)    -   Escherichia coli NCTC 8196 (=EC)    -   Staphylococcus aureus ATCC 9144 (=SA)    -   Candida albicans ATCC 10231 (=CA)

Procedure:

The test substances are pre-dissolved in dimethyl sulfoxide (DMSO) andtested in a dilution series of 1:2.

Bacteria and yeast are cultured overnight in CASO broth.

All the test organism suspensions are adjusted to an organism count of1-5×10⁶ CFU/ml using 85% sodium chloride solution.

The test substances are pre-pipetted into microtitre plates in amountsof 8 μl per well.

The pre-adjusted organism suspensions are diluted 1:100 in CASO brothand are added in amounts of 192 μl per well to the test substances.

The test batches are incubated for 48 hours at 37° C.

The incubation, the growth is determined on the basis of the turbidityof the test batches (optical density) at 620 nm in a microplate reader.

The minimum inhibitory concentration (MIC value) is the concentration ofsubstance at which (compared to the growth of the control) anappreciable inhibition of growth (≦20% growth) of the test organisms isobserved.

Three microtitre plates are used for each test organism and substanceconcentration. All the substances are tested in duplicate.

The microbiological test results are compiled in Table 2: TABLE 2 Comp.of Purity [%] Purity [%] MIC MIC MIC MIC formula 254 nm 280 nm SA EC PACA 3 64 72 7.5 15 >120 7.5 4 37 96 7.5 30 >120 15 5 83 977.5 >120 >120 >120 6 92 97 7.5 60 >120 >120 7 43 48 15 15 >120 30 8 8293 30 30 >120 120 9 94 98 15 15 >120 30 10 49 59 15 30 >120 30 11 75 897.5 15 >120 7.5 12 95 97 7.5 3.75 7.5 7.5 13 94 99 15 15 >120 30 14 9197 15 3.75 30 15 15 91 98 15 >120 >120 >120 16 42 44 7.5 15 >120 15 1739 43 15 30 >120 15 18 42 51 30 30 120 60 19 64 70 7.5 15 >120 8 20 6377 15 30 >120 15 21 70 82 7.5 <3.75 7.5 <3.75 22 51 65 15 15 >120 7.5 2367 82 15 7.5 30 7.5 24 95 97 30 15 30 30 25 88 96 >120 60 >120 120 26 8190 60 60 >120 >120 27 88 93 30 30 >120 60 28 86 93 <3.75 >120 >120 >12029 61 62 15 30 >120 30 30 85 72 60 30 >120 15 31 45 42 60 >120 >120 12032 69 64 60 120 >120 60 33 94 93 30 >120 >120 60 34 89 89 7.5 120 >12030 35 92 88 15 30 120 30 36 82 73 7.5 15 60 7.5 37 82 66 7.5 15 >120 7.538 56 34 <3.75 7.5 >120 <3.75 39 67 46 <3.75 30 >120 15 40 43 4460 >120 >120 120 41 81 77 30 >120 >120 60 42 91 92 <3.75 120 >120 30 4372 68 60 >120 >120 120 44 88 84 120 >120 >120 120 45 82 83 60 >120 >120120 46 88 88 120 >120 >120 120 47 72 67 120 >120 >120 >120 48 81 8530 >120 >120 60 49 92 84 120 >120 >120 >120 50 84 86 120 >120 >120 >12051 77 73 30 >120 >120 >120 52 88 91 30 >120 >120 120 53 87 8960 >120 >120 120 54 90 91 15 >120 >120 120 55 85 87 120 >120 >120 >12056 87 84 60 >120 >120 120 57 99 99 60 >120 >120 120 58 58 78 15 120 >12060 59 34 64 15 60 >120 60 60 46 32 120 >120 >120 120 61 90 87 30120 >120 120 62 66 61 60 120 >120 120 63 99 95 15 30 >120 60 64 80 807.5 30 >120 15 65 96 92 30 60 >120 15 66 90 95 <3.75 30 >120 30 67 48 447.5 30 >120 7.5 68 37 38 15 30 >120 15 69 64 79 <3.75 30 >120 7.5 70 7182 <3.75 15 >120 7.5 71 88 88 7.5 15 >120 7.5 72 79 52 7.5 15 >120 7.573 90 96 <3.75 7.5 >120 <3.75 74 79 39 <3.75 7.5 >120 <3.75 75 92 89 7.515 >120 7.5 76 97 95 15 60 >120 30 77 86 90 7.5 60 >120 15 78 90 94<3.75 7.5 >120 <3.75 79 92 95 <3.75 <3.75 >120 <3.75 80 54 50 <3.757.5 >120 7.5 81 40 42 <3.75 <3.75 >120 <3.75 82 67 84 <3.75 15 >120 7.583 77 72 <3.75 7.5 >120 <3.75 84 93 91 15 15 >120 7.5 85 83 80 15 7.5<120 7.5 86 92 92 15 15 <120 7.5 87 95 94 15 15 <120 7.5 88 95 94 15 15<120 7.5 89 92 90 <3.75 <3.75 >120 <3.75 90 54 33 7.5 15 >120 <3.75 9189 95 30 30 >120 15 92 52 48 <3.75 15 >120 7.5 93 40 39 <3.75 15 >1207.5 94 65 80 <3.75 15 >120 7.5 95 82 83 15 30 >120 15 96 78 85 1530 >120 15 97 31 26 7.5 15 >120 15 98 79 60 15 15 >120 15 99 93 90 1515 >120 30 100 71 59 15 15 >120 15 101 87 78 7.5 7.5 >120 7.5 102 49 257.5 30 >120 15 103 89 89 15 60 >120 30 104 54 41 <3.75 7.5 >120 7.5 10533 38 7.5 15 >120 7.5 106 65 75 <3.75 15 >120 15 107 80 82 7.5 15 >12015 108 87 96 30 >120 >120 >120 109 87 87 15 60 >120 30 110 90 9460 >120 >120 120 111 94 92 7.5 120 >120 60 112 87 90 15 120 >120 30 11392 85 7.5 120 >120 30 114 41 28 15 >120 >120 30 115 93 96 7.5 >120 >120120 116 58 46 7.5 60 >120 15 117 39 40 15 120 >120 30 118 54 70 7.560 >120 15 119 82 87 7.5 >120 >120 120 120 42 35 30 120 >120 30 121 8790 30 >120 >120 >120 122 78 87 30 >120 >120 120 123 68 73120 >120 >120 >120 124 93 96 60 120 >120 60 125 93 93 120 >120 >120 120126 87 86 120 >120 >120 120 127 65 69 60 >120 >120 60 128 46 52120 >120 >120 120 129 58 69 120 >120 >120 120 130 82 83120 >120 >120 >120 131 73 74 120 >120 >120 >120 132 88 9060 >120 >120 >120 133 94 93 15 >120 >120 >120 134 100 89 7.5 >120 >120120 135 92 91 60 120 >120 30 136 92 92 7.5 >120 >120 60 137 49 44 1530 >120 15 138 41 41 30 60 >120 30 139 50 66 7.5 60 >120 30 140 100 8015 >120 >120 120 141 74 71 120 >120 >120 >120 142 100 83 30 >120 >120120 143 84 79 >120 >120 >120 120 144 62 54 60 >120 >120 120 145 4339 >120 >120 >120 120 146 34 35 >120 >120 >120 120 147 61 7360 >120 >120 120 148 72 70 120 >120 >120 >120

Example 11 Agar Incorporation Test CG128e

-   -   Medium: Casein/soymeal peptone agar (Merck)        -   *Sabouraud 4% glucose agar (Merck)    -   Diluent: Sterile 0.85% NaCl solution    -   Incubation: 24 hours at 37° C.        -   *3 days at 28° C.    -   Test solution: 1% stock solutions of all the test substances are        prepared in a suitable solvent and diluted in serial dilutions        to end concentrations of from 1000 ppm to 10 ppm.

Test Principle:

0.3 ml of each dilution step is mixed with 15 ml of nutrient mediumwhile the latter is still liquid. After the nutrient medium hassolidified, 10 μl of each of the following organism dilutions of thetest strains in 0.85% NaCl solution are spotted onto the agar medium:

Microorganisms Used: Staphylococcus aureus ATCC 6538 Staphylococcusaureus ATCC 9144 Staphylococcus epidermidis Corynebacterium xerosis*ATCC 12228 ATCC 373 C. minutissimum ATCC 23348 Propionibacterium acnes(*) ATCC 6919 Escherichia coli NCTC 8196 Escherichia coli ATCC 10536Proteus vulgaris ATCC 6896 Klebsiella pneumoniae ATCC 4352 Salmonellacholeraesuis ATCC 9184 Pseudomonas aeruginosa ATCC 15442 Candidaalbicans ATCC 10231 Aspergillus niger ATCC 6275

The plates are incubated at 37° C. for 24 hours (A. niger at 28° C. for3 days) and then the highest dilution (lowest concentration) of the testsubstance at which growth is just no longer discernible (corresponds tothe MIC) is determined. The results are shown in Table 3. TABLE 3Compound of formula Microorganism (36) (89) (93) Staphylococcus aureusATCC 6538   120 7.5 3.75 Staphylococcus aureus ATCC 9144   120 7.5 3.75Staphylococcus epidermidis ATCC 12228 >120 120 3.75 Corynebacteriumxerosis* ATCC 373    60 3.75 1.88* C. minutissimum ATCC 23348    30 3.751.88 Propionibacterium acnes (*) ATCC 6919    60 3.75 3.75 (*)Escherichia coli NCTC 8196   120 120 120 Escherichia coli ATCC10536 >120 >120 120 Proteus vulgaris ATCC 6896 >120 60 >120 Klebsiellapneumoniae ATCC 4352    60** >120 60 Salmonella choleraesuis ATCC9184 >120 >120 120 Pseudomonas aeruginosa ATCC 15442 >120 >120 >120Candida albicans ATCC 10231 >120 >120 >120 Aspergillus niger ATCC6275 >120 >120 >120

Example 12 “Microbicidal Activity” Suspension Test CG 161/EN1040

Test Method:

-   -   Nutrient medium:        -   Casein/soymeal peptone broth for preparation of pre-cultures            of test bacteria    -   Examples of test organisms:        -   Staphylococcus aureus ATCC 6538        -   Escherichia coli ATCC 10536        -   Actynomyces viscosus ATCC 43146

Procedure:

The test substances are dissolved in dimethyl sulfoxide (DMSO) andtested in a concentration of 120 μg/ml.

Bacteria are incubated overnight in CASO broth and adjusted to anorganism count of 1-5×10⁵ CFU/ml using 0.85% sodium chloride solution.

The test substances are pre-pipetted into microtitre plates in amountsof 8 μl per well.

The adjusted test organism suspensions are added in amounts of 192 μlper well to the test substances and mixed. After defined contact times,the test batches are mixed, an aliquot is withdrawn and diluted inseveral steps in a dilution series of 1:10 in a suitable inactivationmedium.

The test plates are incubated for 24 hours at 37° C. After incubation,the growth is determined on the basis of the turbidity of the testbatches (optical density) at 620 nm in a microplate reader.

On the basis of the number of steps in the dilution series that exhibitgrowth, the reduction in the test organism concentration is determinedin powers of ten (log value).

One microtitre plate is used for each test organism.

All the substances are tested in duplicate.

The results (log reduction) are shown in Table 4: TABLE 4 Compound offormula (93) (93) (89) (89) Organism Contact time 0.12% 120 ppm 0.12%120 ppm S. aureus  5 min >5 1.4 <1 S. aureus 30 min >5 3.8 1.7 E. coli 5 min >5 >5 4.6 E. coli 30 min >5 >5 >5 A. viscosus  5 min >5 2 4.9 3.9A. viscosus 30 min >5 4 >5 4.3

Example 13 Determination of the Minimum Inhibitory Concentration (MICValue) in Microtitre Plates

Nutrient medium and test procedure correspond to Example 10.

As test organisms there are used:

-   -   Staphylococcus aureus ATCC 6538    -   Escherichia coli ATCC 10536    -   Actynomyces viscosus ATCC 43146

Microbiological test results are compiled In Table 5: TABLE 5 Comp. ofPurity [%] Purity [%] formula 254 nm 280 nm MIC SA MIC EC MIC AV 149 9189 120 >120 15 150 87 88 120 >120 60 151 88 86 120 >120 15 152 91 8330 >120 15 153 89 85 120 >120 30 154 94 85 120 120 30 155 85 81 30 307.5 156 86 82 7.5 15 <3.75 157 62 63 15 >120 <3.75 158 86 92 >120 >1207.5 159 89 91 120 >120 30 160 88 92 120 >120 15 161 87 92 120 >120 30162 67 88 120 >120 30 163 67 66 >120 >120 60 164 85 92 120 >120 30 16581 92 >120 >120 30 166 68 75 >120 >120 30 167 92 89 120 120 15 168 7273 >120 >120 15 169 87 83 >120 >120 30 170 77 85 >120 >120 15 171 86 81120 >120 30 172 87 72 60 >120 15 173 69 67 60 60 15 174 66 87 120 >12060 175 69 64 120 120 30 176 82 57 30 30 7.5 177 87 92 120 >120 30 178 7769 120 120 30 179 77 85 120 120 30

1. A method for the antimicrobial treatment of a surface, whichcomprises contacting said surface with an antimicrobially effectiveamount of a 4-aminopyrimidine of formula

R₁ and R₂ are each independently of the other hydrogen; C₁-C₅alkyl whichis unsubstituted or substituted by one or more halogen atoms; biphenylor C₆-C₁₀aryl which is unsubstituted or substituted by halogen,C₁-C₅alkyl, C₁-C₅alkoxy or by amino; a 5- to 7-membered heteroarylradical; or cyclo-C₃-C₇alkyl; R₃ is hydrogen; phenyl or C₁-C₅alkyl whichis unsubstituted or substituted by one or more halogen atoms; R₄ ishydrogen; C₁-C₁₀alkyl; phenyl; or a 5- to 7-membered heteroaryl radical;R₅ is C₁-C₂₀alkyl which is unsubstituted or substituted by one or morehalogen atoms or by a heterocyclic radical or interrupted by one or more—O— or

 groups or by a bivalent heterocyclic radical; NR″R′″-C₁-C₂₀alkyl whichis unsubstituted or substituted by a heterocyclic radical or interruptedby one or more —O— or

 groups or by a bivalent heterocyclic radical; cyclo-C₅-C₈alkyl;hydroxy-C₁-C₂₀alkyl; phenyl-C₁-C₃alkyl; a heterocyclic radical; or R₄and R₅, together with the nitrogen atom linking them, form a radical of

R′ is hydrogen; or C₁-C₃alkyl; R″ and R′″ are each independently of theother hydrogen; C₁-C₅alkyl; or hydroxy-C₁-C₅alkyl; X is

R″″ is hydrogen; C₁-C₄alkyl; or heteroaryl-C₁-C₄alkyl; and n₁ and n₂ areeach independently of the other from 1 to
 8. 2. A method according toclaim 1, wherein R₅ is R″R′″N-C₁-C₂₀alkyl which is uninterrupted orinterrupted by one or more —O— or

 groups or by a bivalent heterocyclic radical; R′ is hydrogen; orC₁-C₅alkyl; R″ and R′″ are each independently of the other hydrogen; ormethyl; and R₁, R₂, R₃ and R₄ are as defined in claim
 1. 3. A methodaccording to claim 1, wherein R₅ is R″R′″N-C₁-C₂₀alkyl which isuninterrupted or interrupted by


4. A method according to claim 1, wherein R₅ is R″R′″N-C₅-C₂₀alkyl whichis uninterrupted or interrupted by one or more —O— or

 groups; R′ is hydrogen; or C₁-C₅alkyl; and R″ and R′″ are eachindependently of the other hydrogen; or methyl.
 5. A method according toclaim 4, wherein R₅ is R″R′″N-C₅-C₂₀alkyl; and R″ and R′″ are eachindependently of the other hydrogen; or methyl.
 6. A method according toclaim 1, wherein R₄ is hydrogen; or C₁-C₅alkyl; R₅ is C₅-C₂₀alkyl whichis unsubstituted or interrupted by —NH—; and R₁, R₂ and R₃ are asdefined in claim
 1. 7. A method according to claim 6, wherein R₁ ishydrogen; C₁-C₅alkyl; unsubstituted or C₁-C₄alkyl-substituted phenyl orphenyl-C₁-C₄alkyl; or pyridino; R₂ is hydrogen; or C₁-C₅alkyl;especially methyl; R₃ is hydrogen; or C₁-C₅alkyl; R₄ is hydrogen; orC₁-C₅alkyl; and R₅ is C₅-C₂₀alkyl.
 8. A method according to claim 6,wherein R₁ is hydrogen; C₁-C₅alkyl; unsubstituted orC₁-C₄alkyl-substituted phenyl; or pyridino; R₂ is methyl; R₃ and R₄ arehydrogen; and R₅ is C₈-C₁₈alkyl.
 9. A method according to claim 6,wherein R₅ is linear C₈-C₁₈alkyl.
 10. A method according to claim 1,wherein, in formula (1a), R″″ is hydrogen; or pyridyl-C₁-C₃alkyl; and n₁and n₂ are in each case
 2. 11. A method according to claim 1, wherein R₁and R₂ are each independently of the other hydrogen; C₁-C₅alkyl; phenylwhich is unsubstituted or substituted by halogen, C₁-C₅alkyl,C₁-C₅alkoxy or by amino; biphenyl; cyclo-C₃-C₇alkyl; 3-pyridyl;4-pyridyl; 2-thiophenyl; 3-thiophenyl; or thiazolyl.
 12. A methodaccording to claim 1, wherein R₃ is hydrogen; or phenyl.
 13. A methodaccording to claim 1, wherein R₄ is hydrogen.
 14. A method according toclaim 1, wherein a compound of formula

wherein X is —O—;

R′ is hydrogen; or C₁-C₃alkyl; n is 1-3; and m is 1-3; and R₁, R₂ and R₃are as defined in claim 1 is employed.
 15. A process for the preparationof a compound of formula (1) according to claim 1, which comprisesreacting 2-amidinopyridine with a keto ester using an auxiliary base ina suitable solvent in accordance with the following scheme:

R₁, R₂, R₃, R₄ and R₅ are as defined in claim
 1. 16. A process for thepreparation of a compound of formula (2) according to claim 14, whichcomprises preparing the compound in a solid-phase synthesis using atrityl (TCP) resin in accordance with the following scheme:

R₁, R₂, R₃, X, m and n are as defined in claim
 14. 17. A methodaccording to claim 1, wherein the compound of formula (1) is used in theantimicrobial treatment, deodorisation and disinfection of the skin,mucosa and hair.
 18. A method according to claim 1, wherein the compoundof formula (1) is used in the treatment of textile fibre materials. 19.A method according to claim 1, wherein the compound of formula (1) isused in preservation.
 20. A method according to claim 1, wherein thecompound of formula (1) is used in washing and cleaning formulations.21. A method according to claim 1, wherein the compound of formula (1)is used in imparting antimicrobial properties to, and preserving,plastics, paper, nonwovens, wood or leather.
 22. A method of a compoundof formula (1) according to claim 1 in imparting antimicrobialproperties to, and preserving, technical products, especially printingthickeners of starch or of cellulose derivatives, surface-coatings andpaints.
 23. A method of a compound of formula (1) according to claim 1as a biocide in technical processes.
 24. A personal care preparationcomprising from 0.01 to 15% by weight, based on the total weight of thecomposition, of a compound of formula (1) according to claim 1, andcosmetically tolerable adjuvants.
 25. An oral composition comprisingfrom 0.01 to 15% by weight, based on the total weight of thecomposition, of a compound of formula (1) according to claim 1, andorally tolerable adjuvants.
 26. A compound of formula

R₁ and R₂ are each independently of the other hydrogen; C₁-C₅alkyl whichis unsubstituted or substituted by one or more halogen atoms; biphenylor C₆-C₁₀aryl which is unsubstituted or substituted by halogen,C₁-C₅alkyl, C₁-C₅alkoxy or by amino; a 5- to 7-membered heteroarylradical; or cyclo-C₃-C₇alkyl; R₃ is hydrogen; phenyl or C₁-C₅alkyl whichis unsubstituted or substituted by one or more halogen atoms; R₄ ishydrogen; C₁-C₁₀alkyl; phenyl; or a 5- to 7-membered heteroaryl radical;R₅ is C₁-C₂₀alkyl which is unsubstituted or substituted by one or morehalogen atoms or by a heterocyclic radical or interrupted by one or more—O— or

 groups or by a bivalent heterocyclic radical; NR″R′″-C₁-C₂₀alkyl whichis unsubstituted or substituted by a heterocyclic radical or interruptedby one or more —O— or

 groups or by a bivalent heterocyclic radical; cyclo-C₅-C₈alkyl;hydroxy-C₁-C₂₀alkyl; phenyl-C₁-C₃alkyl; a heterocyclic radical; or R₄and R₅, together with the nitrogen atom linking them, form a radical of

R′ is hydrogen; or C₁-C₃alkyl; R″ and R′″ are each independently of theother hydrogen; C₁-C₅alkyl; or hydroxy-C₁-C₅alkyl; X is

R″″ is hydrogen; C₁-C₄alkyl; or heteroaryl-C₁-C₄alkyl; and n₁ and n₂ areeach independently of the other from 1 to 8; not including compounds offormula (1′) wherein simultaneously R₁ is C₆-C₁₀aryl; or C₁-C₄alkyl; andR₅ is C₁-C₇alkyl.